Thioether compounds are disclosed useful as pharmaceutical compounds. For example, it is disclosed that a thioether compound having the following chemical structural formula, Viracept (AG1343) has an HIV-1 protease-inhibitory effect and is industrialized as a treating agent for AIDS (see Stephen W. Kaldor, et al., Journal of Medicinal Chemistry, Vol. 40, pp. 3979-3985 (1997)).

Viracept (AG1343)
WO2004/081001 discloses thioether compounds useful as a treating agent and/or a preventing agent for diabetes and also as a treating agent and/or a preventing agent for diabetes complications.
On the other hand, the following method is known for producing thioether compounds (see Nan Zheng, et al., Journal of Organic Chemistry, Vol. 63, p. 9606-9607 (1998)).
In this non-patent reference, as a weak base, K2CO3, NaHCO3 and Triethylamine are used for the reaction, in which, however, the yield of the thioether compound is low, and the method is therefore unsuitable for industrial-scale production. This patent reference 2 says that the production method for thioether compounds disclosed therein is not applicable to a thiol nucleophile such as benzene thiol. In other words, it may be said that the production method could not produce diaryl sulfides.

BaseYield of Compound [A]K2CO357%NaHCO327%triethylamine65%

Further, it is known to produce a thioether compound by the use of a palladium compound such as POPD1, POPD2 or POPD, and a strong base such as KOtBu (see George Y. Li, et al., Journal of Organic Chemistry, Vol. 66, pp. 8677-8681 (2001)).
The palladium compound is poor in universal applicability and is expensive, and therefore the production method for thioether compounds is unsuitable for industrial-scale production.

Also known is a method for producing thioether compounds, using Pd2(dba)3 and DPEphos and, as a base, CsCO3 (see Ulrich Schopfer, et al., Tetrahedron, Vol. 57, pp. 3069-3073 (2001)). According to the production method, the yield of the intended thioether compound is low, and the method is unsuitable for industrial use.

Also known is a method for producing thioether compounds, using Pd(PPh3)4 and t-BuONa (strong base) (see Toshihiko Migita, et al., Bulletin of the Chemical Society of Japan, Vo. 53, pp. 1385-1389 (1980)).

Also known is a method for producing thioether compounds, using CuI and K2CO3 (Fuk Yee Kwong, et al., Organic Letters, Vol. 4, pp. 3517-3520 (2002)).

Also disclosed is a case of producing alkylthioether compounds, starting from an iodine compound (Shyamala Rajagopalan, et al., Synthetic Communications, Vol. 26, No. 7, pp. 1431-1440 (1996)). As starting from an iodine compound, the production method is poor in universal applicability.

Also disclosed is an example of the following reaction case (see JP-A 2002-47278). The yield in the reaction case is too low for industrial-scale production, and the method is unsuitable for industrial use.

For removing a benzyl group or a phenyl group bonding to a thiol group, the following methods are known.
(a) Treatment with metal sodium in liquid ammonia (see J. E. T Corrie, et al., Journal of Chemical Society, Perkin Transaction, Chap. I, p. 1421 (1977)).
(b) Treatment with hydrogen fluoride in anisole (see S. Sakakibara, et al., Bulletin of Chemical Society of Japan, Vol. 40, p. 4126 (1967)).
(c) Electrolysis (see D. A. J. Ives, Canadian Journal of Chemistry, Vol. 47, 3697 (1969)).
The above methods may use reagents dangerous and unsuitable for industrial-scale production that requires use of a large amount of chemicals, and may require specific production equipment such as electrolytic cells, and therefore these are unfavorable for industrial application in some points.
The present invention is to develop a production method capable of efficiently producing a thioether compound or a thiol compound useful as a pharmaceutical compound or a production intermediate of it, as disclosed in Stephen W. Kaldor, et al., Journal of Medicinal Chemistry, Vol. 40, pp. 3979-3985 (1997) and WO2004/081001.